Phenothiazine compounds



United States Patent 3,238,199 PHENOTHIAZINE COMPOUNDS Leo Berger,Montclair, Alfred John Corraz, Packanack Lake, and John Lee, Montclair,NJ., assignors to Hoffmann-La Roche Inc, Nutley, NJ., a corporation ofNew Jersey N0 Drawing. Filed Feb. 27, 1961, Ser. No. 91,603 Claims. (Cl.260-243) 2: This invention relates to novel phenothiazine compoundswhich have utility as medicinal agents. The phenothiazine compounds ofthe invention are characterized by a side chain in the l0-positionwhich, in addition to having an ether linkage, also contains a nitrogenatom. More specifically, the compounds of the invention are of theformula wherein n is a whole integer from 1 to 2; R is selected from thegroup consisting of hydrogen, halogen, and trifluoromethyl; A and B canbe the same or different and are selected from the group consisting ofstraight and branched chain lower alkylene radicals; and R and R areselected from the group consisting of lower alkyl and, taken togetherwith the nitrogen ring, a 5 to 6 membered heterocyclic ring containing 1to 2 nitrogen atoms and a lower alkyl substituted 5 to 6 memberedheterocyclic ring containing 1 to 2 nitrogen atoms.

As used in this disclosure, the term straight or branched chain loweralkylene refers to such radicals as and the like. 5 to 6 memberedheterocyclic rings containing 1 to 2 nitrogen atoms are illustrated byradicals such as piperazinyl, pyrrolidyl, and the like and lower alkylsubstituted 5 to 6 membered heterocyclic rings containing l to 2nitrogen atoms are, for example, 4-methyll-piperazinyl and the like.

The compounds corresponding to Formula I above are basic in characterand form acid addition salts with inorganic or organic acids such ashydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid,methane sul- F fomc acid, toluene sulfomc ac1d, acetic acid, succimcacid, maleic acid, malic acid, tartaric acid, citric acid, benzoic acid,oxalic acid, and the like. These medicinally acceptable acid additionsalts are part of the invention.

Side chains Within the scope of the invention, conforming to thegrouping Patented Mar. 1, 1966 the invention are those under Formula Iabove wherein A represents the group Especially preferred are thosecompounds wherein R and R taken together with the nitrogen atom,represent 4-methyl-1-piperazinyl. Also preferred are those compoundswherein R is trifiuoromethyl.

The novel compounds of the invention can be made by several differentmethods. One method comprises reacting an alkali metal salt of a10-hydroxy-lower alkylene-phcnothiazine with a tertiary amino-loweralkylhalide to yield a IO-tertiary amino-lower alkyleneoxyloweralkylene-phenothiazine. Another method comprises reacting al0-halo-lower alkylene-phenothiazine with a tertiary amino-loweralkanol, in the presence of an alkali metal, such as sodium, to yieldthe desired product corresponding to Formula I above.

The compounds of the invention are valuable medicinal agents, havingutility as anti-emetic agents. They can also be used as central nervoussystem depressants and as potentiators of barbiturate hypnosis. They canbe administered internally, with dosages adjusted to individualrequirements, either as the free base or as a medicinally acceptableacid addition salt. They can be compounded into conventionalpharmaceutical forms such as capsules, .tablets, suspensions, solutionsand the like.

The following examples are illustrative of the invention but notlimitative thereof. All temperatures are in degrees centigrade.

Example 1 A mixture of 150 ml. of dry toluene, 11.6 g. of sodium amide,and 60 g. of phenothiazine was refluxed and stirred for 16 hours, andthe reaction mixture then cooled to 60. 26.1 g. of propylene oxide,dissolved in 150 ml. of dry toluene, was added to the stirring mixtureat such a rate as to maintain the temperature near 60. When the additionhad been completed, the reaction mixture was heated to reflux. After 2hours of refluxing and stirring, the reaction mixture was allowed tocool to room temperature and then washed three times with 100 ml. ofwater and dried over sodium sulfate. The desiccant was removed byfiltration and the filtrate was concentrated under vacuum on a waterbath to a viscous residue. The residue was distilled at reduced pressureto give l0-(2 hydroxypropyl)-phenothiazine as a viscous, light yellowoil; B.P. 161-163 at 0.03 mm.

Example 2 220 g. 2-trifiuoromethylphenothiazine was added rapidly to afine suspension of 20 g. of sodium in 1200 ml. of dry toluene. Whilestirring, the mixture was carefully heated to reflux temperature. After6 hours at reflux with stirring most of the sodium had reacted, and themixture was cooled to 80 g. of propylene oxide in ml. toluene was addedslowly with stirring at such a rate that reaction temperature wasmaintained around 80. With the last third of the addition, externalheating had to be used to maintain 80. After the addition was completed,the reaction mixture was heated with stirring to 100 and held at thattemperature for an additional 2 /2 hours. For approximately 18 hours,the reaction mixture Was allowed to remain at room temperature. It wasthen cooled to +10 with stirring and 60 ml. of ethanol added, followedby 300 ml. of water and 500 ml. of ether. The organic portion wasseparated, washed with 300 ml. of water 5 times, and the solvent layerseparated again and dried over anhydrous sodium sulfate. The desiccantwas removed by filtration, the filtrate concentrated to dryness on awater bath at reduced pressure and the residue was 3 distilled yieldingZ-trifluoromethyl-l-(2-hydroxypropyl) phenothiazine, B.P. 172-175/0.2mm.

2-chloro-10-(Z-hydroxypropyl)phenothiazine, 10 (2-hydroxyethyl)phenothiazine, and 2-chloro-10-(2-hydroxyethyl)phenothiazine were also made by the procedure illustrated in Examples 1and 2 above.

Example 3 A mixture of 100 ml. of dry toluene, 20 g. of10-(2-hydroxyethyl)phenothiazine, and 1.9 g. sodium was refluxed andstirred until all the sodium had reacted, ca. 3 hours. 8.7 g. ofdimethylaminoethyl chloride in 50 ml. of dry toluene was added dropwiseat reflux temperature. After the addition was complete, the reactionmixture was refluxed and stirred for an additional 13 hours, cooled toroom temperature, and filtered. The filtrate was extracted with dilutehydrochloric acid. In turn, the acid extract was washed two times withether and then saturated with potassium carbonate. The alkaline mixturewas then extracted with chloroform. When the chloroform extract had beendried over sodium sulfate for 24 hours, it was filtered and the filtratewas concentrated to a syrupy residue under vacuum. The residue wasdistilled at reduced pressure to give l0-[2-(Z-dimethylaminoethoxy)ethyllphenothi-azine as a viscous oil; BrP. 191-199 at 0.15 mm.

The product was made into an oxalate by dissolving it in ether andadding an excess of an ether-oxalic acid solution. The precipitateformed was crystallized from isopropyl alcohol, M.P. 9496.

Example 4 1.0 g. of sodium was added to a solution of 10.6 g. of10-(2-hydroxyethyl)phenothiazine dissolved in 100 ml. of dry toluene.The mixture was refluxed and stirred until all the sodium had reacted,ca. 2 hours. 7.0 g. of diethylaminoethylchloride in 50 ml. of drytoluene was added dropwise at reflux temperature, with stirring. Afterthe addition was completed, the reaction was refluxed and stirred for anadditional 6 hours, cooled to room temperature and filtered. Thefiltrate was concentrated to dryness and the residue was dissolved in300 ml. of ether. Dry hydrogen chloride was bubbled into the solution.The supernatant mother liquor was decanted and the oily residue waswashed 3 times with ether, then was dissolved in water and the resultingsolution saturated with potassium carbonate and extracted withchloroform. When the chloroform extract had dried over sodium sulfate,it was filtered and concentrated. The residue was distilled at reducedpressure to give 10-[2-(Z-diethylaminoethoxy)ethyl]phenothiazine as ayellow viscous oil; B.P. 193221 at 0.1 mm.

A citrate was made by dissolving the distillate in ether and adding aslight excess of a concentrated citric acidalcohol solution. Theprecipitate was collected and crystallized from acetone and ether, M.P.6768.

Example 20 g. N-(Z-hydroxyethyl)-N'-methyl-piperazine was addeddropwise, very slowly, to 100 ml. of stirring thionyl chloride. Afterthe addition was complete, the reaction was heated cautiously to refluxand held there for 1 hour. The excess thionyl chloride was removed undervacuum on a water bath. 200 ml. of water was carefully added, withstirring, to the residue. The solution was then cooled, saturated withpotassium carbonate, and extracted with ether. After the ether solutionhad dried over sodium sulfate for several hours, it was filtered and thefiltrate concentrated under vacuum on a water bath. The residue wasdissolved in 50 ml. of dry toluene and the solution was added to arefluxing and stirring mixture of 16.3 g. of the sodium salt of-(2-hydroxyethyl)phenothiazine in 100 ml. of dry toluene. After thereaction had refluxed and stirred for 16 hours, it was cooled to roomtemperature and washed by extraction with water. The

reaction was then extracted with dilute hydrochloric acid. In turn, theacid extract was washed with ether and saturated with potassiumcarbonate. The alkaline mixture that formed was then extracted withether. After the ether solution had been dried over sodium sulfate, itwas filtered, and a slight excess of an ether solution of maleic acidwas added. The precipitate was filtered and recrystallized from ethanolto give 10-{2-[2*(4-methyl1- piperazinyl)ethoxy]ethyl}phenothiazinedimaleate, M.P. l64-166 (uncorr.).

Example 6 Phenyl lithium was prepared from 50 g. of brornobenzene and4.2 g. of lithium wire in 300 cc. of dry ether; 53.7 g. of phenothiazinewas then added. The mixture was stirred at room temperature for 1 hourand ether then added to thin the thick mixture which was then cooledwith ice-water. When cool 67.0 g. of 3-chloro-n-propy1-ptoluenesulfonate in cc. ether was added. Upon completion of the addition, thereaction mixture was heated toreflux for 2 hours and then cooled,reacted with cold water, and the ether solution separated after washingwith water. The ether solution was then dried and concentrated todryness and the residue crystallized with ethanol to give10-(3-ch-loropropyDphenothiazine as crystals melting at 63-64".

Example 7 5.9 g. of diethylarn-inoethanol was reacted with 1.2 g. sodiumshot in 100 cc. of dry toluene under reflux. 13.7 g. of3-chloropropylphenothiazine in 50 cc. of warm toluene was then added andthe mixture stirred under reflux for 24 hours, cooled to roomtemperature and filtered. The filtrate was extracted with dilutehydrochloric acid. In turn, the acid extract was washed with ether andthen saturated with potassium carbonate. The product was isolated byextracting the aqueous mixture with chloroform. After the chloroformsolution had been dried over potassium carbonate, it was filtered andconcentrated under vacuum on a water bath to a viscous oil, which wasthen distilled to give the product, 10-[3-Z-diethylaminoethoxy)propyl]phenothiazine, as an oil boiling at 200/.02mm. Conversion to a citrate salt in alcohol-ether, yielded crystalswhich, after further recrystallization from acetone, melted at 8890.

Example 8 4.5 g. of dimethylaminoethanol was added to 1.2 g. of sodiumshot in 100 cc. of dry toluene and the mixture refluxed until the sodiumhad reacted. To this suspension was added 13.7 g. of3-chloropropylphenothiazine in 500 cc. of dry toluene and the mixturestirred and refluxed for 24 hours. Alcohol and water were then added andbasic material separated with hydrochloric acid solution. The acidsolution was made basic and the oil that separated was dissolved inchloroform, Washed with water, the chloroform layer separated and dried.The resulting dried chloroform solution was concentrated to dryness andthe residue distilled. An oil boiling at 196/ 0.03 mm. was collectedwhich was dissolved in acetone and converted to a hydrochloride withalcoholic hydrochloric acid. Ether was added to induce crystallization.Crystals of 10[3-(Z-dimethylaminoethoxy)propyl]phenothiazinehydrochloride were obtained.

Example 9 7.2 g. of 1-methyl-4-hydroxyethyl-piperazine was reacted With1.2 g. of sodium shot in 100 cc. of boiling toluene. 13.7 g. of3-chloropropylphenothiazine in 50 cc. warm toluene was added and themixture refluxed and stirred for 24 hours, then cooled to roomtemperature and filtered. The filtrate was extracted with dilutehydrochloric acid, and the acid extract washed with ether and saturatedWith potassium carbonate. The product was isolated by extracting theaqueous mixture with chlo roform. After the chloroform solution had beendried over potassium carbonate, it was filtered and concentrated undervacuum on a water bath to a thick syrup that did not distill at 0.08 mm.This thick basic residue was converted to a hydrochloride salt inalcohol with alcoholic hydrochloric acid and recrystallized from ethylacetate-methanol, yielding crystals of -{3-[2-(4-methyll-piperazinyl)ethoxy] propyl}ph-enothiazine dihydrochloride melting at 201202.

Example 10 3.3 g. of diethylaminopropanol was added to 0.06 g. of sodiumin 100 cc. of dry toluene and the mixture refluxed until all the sodiumhad reacted. 6.9 g. of 3- chloropropylphenothiazine in 20 cc. of warmtoluene was then added and the mixture stirred and refluxed for 24hours. 100 cc. of ethanol was then added and the basic oil was extractedwith 6 N hydrochloric acid. The acid layer was separated, made basicwith excess potassium carbonate, and the basic oil extracted with ether.The ether solution was washed with water, dried, and concentrated todryness. The thick residue was converted to the citrate,10-[3-(3-diethylaminopropoxy)propyl]phenothiazine citrate, in alcoholand acetone, and recrystallized from acetone to give crystals melting at76.

Example 11 5.7 g. of dimethylaminoethoxyethanol was added to 1.2 g. ofsodium shot in 100 cc. of dry toluene and the mixture was refluxed untilall the sodium had reacted. 13.7 g. of 3-chloropropylphenothiazine in 50cc. of warm toluene was then added and the mixture stirred under refluxfor 8 hours, cooled to room temperature and filtered. The filtrate wasextracted with dilute hydrochloric acid and the acid extract washed withether and then saturated with potassium carbonate. The product wasisolated by extracting the aqueous mixture with chloro form. After thechloroform solution had been dried over potassium carbonate, it wasfiltered and concentrated under vacuum on a water bath to a viscous oil,which was distilled to yield an oil boiling at 205207/0.07 mm. Thisbasic oil was converted to a hydrochloride salt with alcoholichydrochloric acid and recrystallized from ethyl acetate-methanol toyield crystals of 10-{3-[2-(2-dimethylaminoethoxy)ethoxy]propyl}phenothiazine hydrochloride melting at122.5-123 Example 12 8.1 g. of diethylaminoethoxyethanol was added to1.2 g. of sodium shot in 100 cc. of dry toluene and the mixture refluxeduntil all the sodium had reacted. 13.7 g. of 3-chloropropylphenothiazinein 50 cc. of warm toluene was then added and the mixture stirred andrefluxed for 8 hours, then cooled to room temperature and filtered. Thefiltrate was extracted with dilute hydrochloric acid and the acidextract washed with ether and then saturated with potassium carbonate.The product was isolated by extracting the aqueous mixture withchloroform. After the chloroform solution had been dried over potassiumcarbonate, it was filtered and concentrated under vacuum on a water bathto a viscous oil, which was then distilled in vacuum yielding, as athick oil boiling at 2l2219/0.08 mm.,l0{3-[2-(2-diethylaminoethoxy)ethoxy] propyl}pher1othiazine citrate,which gave an amorphous hydrochloride. A crystalline citrate wasprepared and when recrystallized from acetone, crystals of the citratemelting at 98l00 were obtained.

Example 13 1.0 g. of sodium was added to a solution of 11.0 g. of10-(2-hydroxypropyl)phenothiazine in 100 ml. of dry toluene. All thesodium had reacted after the solution had been stirred and refluxed for1 hour. 5.0 g. of freshly distilled dimethylaminoethylchloride in 50 ml.of dry toluene was then added dropwise, with stirring, at

reflux temperature. The reaction mixture was then stirred and refluxedfor an additional 18 hours, cooled to room temperature and filtered. Thefiltrate was extracted with dilute hydrochloric acid. In turn, the acidextract was washed with ether and then saturated with potassiumcarbonate. The product was isolated by extracting the aqueous mixturewith chloroform. After the chloroform solution had been dried overpotassium carbonate, it was filtered and concentrated under vacuum on awater bath to a viscous oil. The oil was then distilled under vacuum togive 10-[2-(2-dimethylaminoethoxy)propyl]phenothiazine as a viscouslight yellow oil; B.P. 190192 at 0.15 mm. An oxalate was made of theproduct by dissolving the oil in ether and adding a slight excess of anoxalic acid-ether solution. The precipitate that formed wasrecrystallized from acetone and ether.

Example 14 0.9 g. of sodium was added to a solution of 10 g. of10-(2-hydroxypropyl)phenothiazine dissolved in ml. of dry toluene. Themixture was refluxed and stirred until all the sodium had reacted, ca. 2hours. 6 g. of freshly distilled diethylaminoethylchloride dissolved in100 ml. dry toluene was added dropwise at reflux temperature. After thisaddition, the reaction mixture was refluxed for 3 hours and allowed tostand at room temperature overnight. The reaction mixture was filtered.The filtrate was concentrated under vacuum on a water bath to a viscousoil, which was distilled; B.P. 187-192" at 0.07 mm., yielding10[2-(2-diethylaminoethoxy)propyl]-phenothiazine as a light yellow,viscous oil. A solid product was prepared by dissolving the base inether and adding a slight excess of a concentrated alcoholic solution ofcitric acid. The citrate was crystallized 2 times from acetone andether.

Example 15 20.0 g. N-(Z-hydroxyethyl)-N-methyl-piperazine was addeddropwise, very slowly at 100 ml. of stirring thionylchloride. After theaddition was completed, the reaction was heated cautiously to reflux andheld there for 1 hour. The excess thionylchloride was removed undervacuum on a water bath. 200 ml. of water was carefully added, withstirring, to the residue. The solution was then cooled, saturated withpotassium carbonate, and extracted with ether. After the ether solutionhad been dried several hours over sodium sulfate, it was filtered andconcentrated, under vacuum, on a water bath. The syrupy residue wasdissolved in 50 ml. of dry toluene, and the resulting solution added toa refluxing and stirring mixture of 100 ml. of dry toluene and 11.0 g.of the sodium salt of 10-(2-hydroxypropyl)phenothiazine, previously madeby reacting stoichiometric amounts of metallic sodium and10-(2-hydroxypropyl)phenothiazine in dry toluene. When the reactionmixture had refluxed and stirred 8 hours, it was cooled to roomtemperature and washed with water. The organic portion was thenextracted with dilute hydrochloric acid. In turn, the acid extract waswashed with ether and saturated with potassium carbonate. The productwas collected by extracting the aqueous mixture with ether. After theether solution had dried over sodium sulfate, it was filtered andconcentrated under vacuum on a water bath, to a viscous residue. Thecrude product was dissolved in dry ethanol, boiled with charcoal andfiltered. A slight excess of a citric acid-ethanol solution was added.'In order to induce precipitation, several volumes of ether were added.The precipitate that formed was filtered off and recrystallized fromisopropanol yielding10-{2-[2-(4-methyl-1-piperazinyl)ethoxy]propyl}phenothiazine citrate,M.P. 87-89 (uncorr.).

Example 16 0.9 g. of sodium was reacted at reflux temperature with 11.4g. of 2 chloro 10(2 hydroxyethyl)phenothiazine that had been dissolvedin 100 cc. of dry toluene. The reaction mixture was refluxed and stirreduntil all the sodium had reacted, ca. 3 hours. 6.0 g. ofdiethylaminoethylchloride dissolved in 20 ml. of dry toluene was addeddropwise, with stirring, at reflux temperature. After the addition wascomplete, the reaction mixture was refluxed and stirred for anadditional 8 hours, cooled to room temperature and filtered. Thefiltrate was extracted with dilute hydrochloric acid. In turn, the acidfraction was washed with ether and saturated with potassium carbonate.The product was collected by extracting the aqueous mixture withchloroform. After the ether solution had been dried over potassiumcarbonate, it was filtered and concentrated under vacuum to an oilyresidue. The oil was distilled at reduced pressure to give 2-chloro-l0-[2-(2-diethylaminoethoxy)ethyl]phenothiazine as a light yellow, viscousoil; B.P. 210214 at 0.15 mm.

A citrate of the reaction product was made by dissolving the distillatein ether and adding a slight excess of a concentrated citricacid-alcohol solution. The precipitate was collected on a filter andcrystallized from acetone and ether yielding the crystals of the citratesalt.

Example 1 7 3.8 g. of dimethylaminoethanol was dissolved in 50 ml. ofdry toluene. To this solution 1.0 g. of sodium was added. The mixturewas refluxed and stirred until all the sodium had reacted, ca. 2 hours.Following the introduction of 15 g. of crude2-chloro-10-(3-chloropropyl)- phenothiazine dissolved in 50 cc. of drytoluene, the reaction mixture was refluxed and stirred for an additional16 hours and then allowed to cool to room temperature. 200 ml. ofbenzene was added and the resulting mixture washed 2 times with water.The organic portion was then extracted with dilute hydrochloric acid. Inturn, the acid fraction was washed with ether and then saturated withpotassium carbonate. The product was collected by extracting the aqueousmixture with chloroform. After the chloroform solution had been driedover sodium sulfate, it was filtered and concentrated under vacuum on awater bath to a viscous residue. The residue was distilled at reducedpressure to give 2-chloro-l0- [3 (2dimethylaminoethoxy)propyl]phenothiazine as a viscous oil; B.P.175200/-0.2 mm. A citrate was made from the product by dissolving theoil in ether and adding a slight excess of a citric acid-alcoholsolution. The precipitate formed was crystallized from acetone.

Example 18 g. of 2-chlorophenothiazine was dissolved in 100 m1. of drytoluene. To this solution 4.0 g. of sodium amide was added. The mixturewas refluxed and stirred for 6 hours. 10 g. of trimethylenebromochloridewas added. The reaction was again allowed to reflux and was stirred foran additional 6 hours. When the reaction had cooled to room temperature,10 ml. of ethanol was added with stirring followed by 200 ml. of Waterand 100 ml. of benzene. The organic layer was separated and washed withwater. After the chloropropylphenothiazine solution had dried oversodium sulfate, it was filtered and concentrated to a syrup. The syrupresidue was, in turn, dissolved in 50 ml. of dry toluene and added, at areflux temperature, to a stirring mixture of 8.0 g. of the sodium saltof N-(2-hydroxyethyl)-N-methylpiperazine previously made by reactingstoichiometric amounts of metallic sodium andN-(Z-hydroxyethyl)-N'-methylpiperazine in refluxing dry toluene. Afterthe reaction mixture had stirred and refluxed for 10 hours it was cooledto room temperature. 5.0 ml. of ethanol was then added with stirringfollowed by 100 ml. of water and 200 ml. of ether. The organic layer wasseparated and washed with water. It was then extracted with dilutehydrochloric acid. The acid portion was, in turn, saturated withpotassium carbonate and the product collected by an ether extraction.After the ether solution had dried over sodium sulfate, it was filteredand concentrated. The filtrate was distilled at reduced pressure to give2-chloro- 10 {3 [2 (4 methyl 1 piperazinyl)ethoxy1propyl} phenothiazineas a viscous oil; B.P. 120-122" at 0.35 mm.; however, there wasconsiderable decomposition during the distillation. The crude oil wasthen dissolved in ether and a slight excess of a citric acid-alcoholsolution was added. The product formed was crystallized from acetone,M.P. 120122 (uncorr.).

Example 19 10.0 g. of 2-chloro-1-(Z-hydroxypropyl)phenothiazine wasdissolved in ml. of dry toluene. To this solution, 0.8 g. of sodium wasadded. The mixture was refluxed and stirred until all the sodium hadreacted, ca. 3 hours. 7.0 g. of dimethylaminoethylchloride dissolved in50 ml. of dry toluene was added dropwise, with stirring, to therefluxing reaction mixture. After all the dimethylaminoethylchloride hadbeen introduced, the reaction was refluxed and stirred for an additional11 hours, cooled to room temperature and filtered. The filtrate wasextracted with dilute hydrochloric acid. In turn, the acid fraction waswashed with ether and then saturated with potassium carbonate. Theproduct was collected by extracting the aqueous mixture with ether.After the ether solution had been dried over potassium carbonate, it wasfiltered and the filtrate was concentrated under vacuum to give aviscous residue. The residue was distilled at reduced pressure to give2-chloro-l0-[2-(Z-dimethylaminoethoxy) propyllphenothiazine as a viscousyellow oil; B.P. 191- 200 at 0.08 mm. A citrate was made by dissolvingthe oil in ether and adding a slight excess of a citric acidalcoholsolution. The precipitate that formed was crystallized from acetone;M.P. 9395 (uncorr.).

Example 20 15.0 of 2-chloro-l0-(2-hydroxypropyl)phenothiazine wasdissolved in 70.0 ml. of dry toluene. To this solution 2.0 g. of sodiumamide was added. The resulting mixture was refluxed and stirred for 2hours. Then, 23.6 g. of N-(Z-chloroethyl)- I'-methylpiperazine was addedwith stirring at reflux temperature. After the reaction had refluxed andstirred for 7 hours, it was allowed to cool to room temperature. 200 ml.of water followed by 300 ml. of ether was added to the stirring mixture.The organic portion was separated and extracted with dilute hydrochloricacid. In turn, the acid extract was washed with ether and saturated withpotassium carbonate. The product was collected by extracting thealkaline mixture with ether. After the ether solution had dried over potassium carbonate, it was filtered and concentrated under vacuum, on awater bath, to a syrup. The syrup was distilled at reduced pressure togive 2-chloro-l0{2-[2-(4-methyl-l-piperazinyl)ethoxy]propyl}phenothiazine as a light yellowviscous oil; B.P. 200-220 at 0.3 mm. A hydrochloride was made bydissolving the base in ether and saturating the ether solution with dryhydrochloride. The precipitate was crystallized from a combination ofmethanol and ethyl acetate and gave the hydrochloride salt; M.P. 239-240(uncorr.).

The N-(2-chloroethyl)-N-methylpiperazine used above was made by reacting25.0 g. of N-(2-hydroxyethyl)-N'- methylpiperazine hydrochloride in a100 ml. of refluxing thionyl chloride. The excess thionyl chloride wasremoved under vacuum, on a water bath, and the residue was dissolved in100 ml. of water, saturated with potassium carbonate, and extracted withether. After the ether solution had dried over sodium sulfate forseveral hours, it was filtered and concentrated, yielding N-(2-chloroethyl)-N-methylpiperazine as a syrup.

Example 21 12.0 g. of 2-chloro-l0-(2-hydroxypropyl)phenothiazine wasdissolved in 100 cc. of dry toluene. To this solution 1.7 g. of sodiumamide Was added. After the reaction mixture had stirred and refluxed for2 hours, 10.0 g. of dimethylarninoisopropylchloride dissolved in 25.0ml. of dry toluene was added dropwise at reflux temperature. When thereaction had refluxed and stirred an additional 10 hours, it was allowedto cool to room temperature. 20.0 ml. of ethanol was added withstirring, followed by 200 ml. of water and 200 ml. of ether. The organiclayer was separated, washed with ether and extracted with dilutehydrochloric acid. In turn, the acid extract was washed with ether andthen saturated with potassium carbonate. The product was collected byextracting the aqueous mixture with ether. After the ether solution haddried over potassium carbonate, it was filtered and concentrated undervacuum, on a water bath, to a viscous residue. The residue was distilledat reduced pressure to give2-chloro-10-[2-(Z-dimethylaminoisopropoxy)propyl]phenothiazine as aviscous oil; B.P. 202- 207 at 0.2 mm. A citrate was made by dissolvingthe base in ether and adding a slight excess of a citric acidalcoholsolution. The precipitate was crystallized by dissolving it in acetone,filtering, and adding several volumes of ethyl acetate; M.P. 7879(uncorr.).

Example 22 0.85 g. of sodium was added to a solution of 11.2 g. ofZ-trifluoromethyl-10-(2-hydroxypropyl)phenothiazine in 50 ml. of drytoluene. The mixture was refluxed and stirred until all the sodium hadreacted, ca. 13 hours. Then, 25 g. ofN-(2-chloroethyl)-N'-methylpiperazine (made by reacting 44 g.N-(Z-hydroxyethyl)-N'-methylpiperazine hydrochloride with 200 ml. ofthionyl chloride at reflux temperature), in 50 ml, of dry toluene, wasadded at reflux temperature with stirring. The reaction mixture wasrefluxed and stirred an additional 10 hours. After the reaction hadcooled to room temperature, 20 ml. of ethanol was added with stirring,followed by 200 ml. of water and 300 m1. of benzene. The organic portionwas separated and in turn washed two times with 100 ml. of water andthen extracted with dilute hydrochloric acid. The acid extract waswashed once with ether and then saturated with potassium carbonate.Finally, the alkaline mixture was extracted with ether. After the ethersolution had dried over sodium sulfate, it was filtered andconcentrated. The residue was distilled at reduced pressure to giveZ-trifluoromethyl-lO-{Z- [2-(4-methyl-1-piperazinyl)ethoxy]propyl}phenothiazine, B.P. 185190 at 0.25 mm.

A citrate was made by dissolving the base in ether and adding a slightexcess of an alcoholic solution of citric acid. The precipitate wascrystallized from acetone yielding crystals of the salt melting at150-152 (uncorr.).

Example 23 N-(Z-chloroethyl)pyrrolidine was made by reacting 67 g. ofN-(2-hydroxyethyl)pyrrolidine hydrochloride in 200 ml. of refluxingthionyl chloride. The excess thionyl chloride was removed under vacuumon a water bath. The residue was dissolved in 200 ml. of water plus 100g. of ice, saturated with potassium carbonate, and extracted with ether.After the solution had dried over sodium sulfate for several hours, itwas filtered and concentrated yielding crudeN-(2-chloroethyl)-pyrrolidine as a syrup.

Example 24 A mixture of 52 g.Z-trifluoromethyl-l-(2-hydroxypropyl)-phenothiazine, 120 ml. drytoluene, and 6.2 g. of sodium amide was stirred at room temperature for0.5 hour and then heated slowly to reflux. After all the sodium amidehad reacted (ca. 2 hours), 58 g. of crude N-(2-chloroethyl)pyrrolidinein 80 ml. of dry toluene was added dropwise with stirring at refluxtemperature. After the reaction had refluxed and stirred for 12 hours,it

was allowed to cool to room temperature. 150 ml. of water and 2000 ml.of ether were added to the stirring mixture. The organic portion wasseparated and extracted with dilute hydrochloric acid. In turn, the acidextract was washed with ether, saturated with potassium carbonate, andextracted again with ether. After the ether extract had dried overpotassium carbonate, it was filtered and concentrated to a viscous syrupunder vacuum. The residue was distilled, giving 2-trifluoromethyl-10-{2-[2-(l-pyrrolidyl)-ethoxy]propyl}phenothiazine as a glassy solid; B.P.199200/O.2 mm., a 1.5674. The hydrochloride was obtained by dissolvingthe distillate in ether and bubbling dry hydrogen chloride into thesolution. A mixture of ethyl acetate and methanol was used tocrystallize the crude hydrochloride; M.P. 164-165" (uncorr.).

Example 25 2.4 g. of sodium amide was added to a solution of 20 g. of2-trifluoromethyl-10-(Z-hydroxypropyl)phenothiazine in ml. of drytoluene. The resulting mixture was carefully heated (someeffervescence), with stirring, to reflux. After the reaction hadrefluxed and stirred for 2 hours and all the sodium amide had reacted,20 g. dimethylaminoethyl chloride in 100 ml. of dry toluene was addeddropwise. The mixture was allowed to reflux and was stirred for anadditional 18 hours. When the reaction mixture had cooled to roomtemperature, 10 ml. of ethanol was added with stirring, followed by 100ml. of water and 200 ml. of ether. The organic portion was separated,washed with water, and then extracted with dilute hydrochloric acid. Inturn, the acid extract was washed with ether, saturated with potassiumcarbonate, and again extracted with ether. After the ether extract haddried over sodium sulfate, the desiccant was removed by filtration andthe filtrate concentrated under vacuum on a water bath. The syrupyresidue was distilled at reduced pressure to give Z-trifluoromethyl-IO-[2-( Z-dimethylaminoethoxy )propyl1phenothiazine as a light yellow,viscous oil, B.P. 176177/0.05 mm. A citrate was made by dissolving thedistillate in 300 ml. acetone and adding 8 g. of citric acid in 10 ml.of water. In order to induce crystallization, the solution wasconcentrated to dryness and 300 ml. of fresh acetone was added. Thesolution was set in the refrigerator for several days and then filtered;the resulting citrate melted at 102104 (uncorr.).

We claim:

1. 2-trifluoromethyl-10-{2-[(4-lower alkyl 1 piperazinyl -loweralkyleneoxy] -propyl}-phenothiazine.

2. A compound selected from the group consisting of compounds of theformula sisting of straight and branched chain lower alkylene radicals;the moiety is selected from the group consisting of unsubstituted andlower alkyl-substituted l-pyrrolidyl, l-piperazinyl and l-piperidinyl.

3. 2-trifluoromethyl-10-{2-[2-(1-pyrrolidyl)-lowerkyleneoxy]propyl}-phenothiazine.

4. 2 trifluoromethyl-lO-{Z-[2-(1-pyrr01idy1)-ethoxy]-propyl}-phenothiazine.

5. Z-trifluorornethyl-lO-{Z-[2-(4-methyl-1-piperaziny1)-ethoxy]-propy1}-phenothiazine citrate.

References Cited by the Examiner UNITED STATES PATENTS Cusic 260243 VonSeemann 260-243 Jacob et a1 260243 Gailliot et a1 260243 Gailliot et a1.260243 Jacob et a1. 260243 12 2,928,767 3/1960 Gulesich et a1. 2602432,976,286 3/1961 Schindler et a1. 260243 FOREIGN PATENTS 5 213,4022/1961 Australia.

786,384 11/1957 Great Britain.

OTHER REFERENCES Schmitt et a1.: Bull. Soc. Chim., France, 1957, page 10939.

WALTER A. MODANCE, Primary Examiner.

IRVING MARCUS, Examiner.

1. 2-TRIFLUOROMETHYL-10-(2-((4-LOWER ALKYL - 1 - PIPERAZINYL)-LOWER ALKYLENEOXY)-PROPYL)-PHENOTHIAZINE.
 2. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF COMPOUNDS OF THE FORMULA 